B-cell dysfunction is a hallmark of HIV/SIV infection that begins very early in infection even before CD4 T cell depletion. Increasing evidence suggests that heightened B-cell activation, lack of memory B-cell restoration and impaired vaccine induced antibody responses persists even in patients receiving suppressive anti- retroviral therapy. Even though our understanding of B-cell dynamics in HIV/SIV infection has significantly improved, the molecular mechanisms underlying B-cell dysfunction remain poorly understood. In addition to cytokines and transcription factors, recent studies show miRNA-mediated gene regulation to be critical for B- cell differentiation, maturation, activation and autoimmune responses. Extensive studies in autoimmune diseases associated with B-cell defects have revealed a causative role for microRNAs in disease pathogenesis resulting in their identification as promising therapeutic targets. However, the role of miRNAs in HIV induced B-cell dysfunction is lacking. Our preliminary studies for this application identified significant dysregulation of miRNAs linked to B-cell activation and lymphomagenesis in purified B-cells from chronically SIV-infected macaques. Interestingly and more importantly, chronic THC treatment to SIV-infected macaques markedly inhibited their expression suggesting their immense therapeutic potential for attenuating immune (B-cell) activation and slowing disease progression. Based on our strong preliminary data demonstrating that miRNA expression is dysregulated in B-cells in HIV/SIV infection, we hypothesize that this leads to B-cell dysfunction which contributes to immune activation and HIV disease progression. Further, we hypothesize that chronic ?9- THC treatment may reduce inflammation, restore immune (B-cell) function, and slow HIV/SIV disease progression by modulating miRNA expression. A major goal of this application is to identify miRNA mechanisms associated with B-cell dysfunction and cannabinoid mediated suppression of B-cell activation. The project has three specific aims: 1) Test the hypothesis that miR-34a and miR-155 targeting of SIRT1 leads to enhanced acetylated-p65 and acetylated-FOXO3a expression, causing B-cell hyperactivity and apoptosis, respectively. 2) Identify miRNA mechanisms of cannabinoid induced suppression of B-cell activation in blood, lymph nodes, and intestine at three different time points following SIV infection. 3) Determine the effect of combination anti-retroviral treatment (cART) in conjunction with chronic ?9-THC administration on inflammation, chronic immune activation, viral replication, miRNA expression, SIRT1 levels, B-cell activation and apoptosis. The proposed research is novel and applies state of the art immunological and molecular approaches to address a significant gap in our understanding of the post-transcriptional mechanisms underlying B-cell dysfunction. Additionally and more importantly, the results will deepen our understanding of the mechanisms underlying the anti-inflammatory effects of cannabinoids and have important therapeutic implications for targeted immune modulation in HIV and other autoimmune diseases with B-cell defects.